RESUMEN
Multiple host and microbial factors dictate whether Candida albicans can colonize the mammalian gastrointestinal tract. In this issue of Cell Host & Microbe, Savage et al. demonstrate that restoration of intestinal epithelial hypoxia is sufficient to restore Candida albicans colonization resistance, even when other Candida inhibitory effectors remain depleted.
Asunto(s)
Candida albicans , Candidiasis , Tracto Gastrointestinal , Candida albicans/crecimiento & desarrollo , Candida albicans/fisiología , Humanos , Tracto Gastrointestinal/microbiología , Candidiasis/microbiología , Animales , Hipoxia/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismo , Ratones , Interacciones Huésped-Patógeno , Microbioma Gastrointestinal/fisiologíaRESUMEN
Peripheral CD8+ T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8+ T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects.
Asunto(s)
Linfocitos T CD8-positivos , Diferenciación Celular , Tolerancia Inmunológica , Biosíntesis de Proteínas , Receptores de Antígenos de Linfocitos T , Linfocitos T CD8-positivos/inmunología , Animales , Diferenciación Celular/inmunología , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Tolerancia Inmunológica/inmunología , Biosíntesis de Proteínas/inmunología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Autoantígenos/inmunologíaRESUMEN
The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T cells (Treg), which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediated Treg plasticity toward a TH17-like Treg phenotype, resulting in increased IL17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Proteínas Proto-Oncogénicas c-bcl-2 , Sulfonamidas , Linfocitos T Reguladores , Células Th17 , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratones , Células Th17/inmunología , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Línea Celular Tumoral , Ratones Endogámicos C57BL , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Adaptive immunity relies on specialized effector functions elicited by lymphocytes, yet how antigen recognition activates appropriate effector responses through nonspecific signaling intermediates is unclear. Here we examined the role of chromatin priming in specifying the functional outputs of effector T cells and found that most of the cis-regulatory landscape active in effector T cells was poised early in development before the expression of the T cell antigen receptor. We identified two principal mechanisms underpinning this poised landscape: the recruitment of the nucleosome remodeler mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) by the transcription factors RUNX1 and PU.1 to establish chromatin accessibility at T effector loci; and a 'relay' whereby the transcription factor BCL11B succeeded PU.1 to maintain occupancy of the chromatin remodeling complex mSWI/SNF together with RUNX1, after PU.1 silencing during lineage commitment. These mechanisms define modes by which T cells acquire the potential to elicit specialized effector functions early in their ontogeny and underscore the importance of integrating extrinsic cues to the developmentally specified intrinsic program.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas Proto-Oncogénicas , Proteínas Represoras , Transactivadores , Factores de Transcripción , Proteínas Supresoras de Tumor , Proteínas Proto-Oncogénicas/metabolismo , Animales , Transactivadores/metabolismo , Transactivadores/genética , Ratones , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Ratones Endogámicos C57BL , Proteínas Cromosómicas no Histona/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Ratones Noqueados , Ensamble y Desensamble de Cromatina , Diferenciación Celular/inmunologíaRESUMEN
Antibiotic resistance and evasion are incompletely understood and complicated by the fact that murine interval dosing models do not fully recapitulate antibiotic pharmacokinetics in humans. To better understand how gastrointestinal bacteria respond to antibiotics, we colonized germ-free mice with a pan-susceptible genetically barcoded Escherichia coli clinical isolate and administered the antibiotic cefepime via programmable subcutaneous pumps, allowing closer emulation of human parenteral antibiotic dynamics. E. coli was only recovered from intestinal tissue, where cefepime concentrations were still inhibitory. Strikingly, "some" E. coli isolates were not cefepime resistant but acquired mutations in genes involved in polysaccharide capsular synthesis increasing their invasion and survival within human intestinal cells. Deleting wbaP involved in capsular polysaccharide synthesis mimicked this phenotype, allowing increased invasion of colonocytes where cefepime concentrations were reduced. Additionally, "some" mutant strains exhibited a persister phenotype upon further cefepime exposure. This work uncovers a mechanism allowing "select" gastrointestinal bacteria to evade antibiotic treatment.